EVGN scientists from the group of Professor Theo J.C. Van Berkel, at the Division of Biopharmaceutics, Leiden/Amsterdan Center for Drug research, Leiden University (The Netherlands), identified two molecular transporters that appear essential in the maintenance of lipid equilibrium (or homeostasis) in macrophages, cells whose behavior – if unbalanced - may contribute to generate atherosclerotic lesions. Improper functioning of these two transporters does occur, observe the scientists, but we could, in principle, think of correcting it, offering in this way a potential new strategy to prevent lipid accumulation which is a typical atherosclerosis phenomenon. The research was published in the February 11th issue of the journal Circulation Research.

Keeping the appropriate balance in biochemical reactions or cellular activity is essential for the human organism, and a good example is represented by macrophages. These cells behave like scavengers in that they remove cholesterol from atherosclerotic lesions. However, the fate of cholesterol that enters their cellular body determines whether they help or hinder cholesterol removal from the vessel wall. If the healthy equilibrium between the uptake and the efflux of cholesterol is perturbed, these cells become foamy and start producing chemical factors that promote atherosclerosis.

The Dutch group led by Theo J.C. Van Berkel was studying the mechanisms that regulate the inward/outward flux of cholesterol in macrophages. From previous studies it was known that two cholesterol transporters called ABCA1 and ABCG1 act sequentially to remove this substance from the cells. “However, we ignored what their role was in vivo” pinpoints Ruud Out, first author of the paper together with colleagues Wendy Jessup and Wilfried Le Goff. “To clarify whether these transporters were cooperating, or alternatively, working individually – adds Out - we devised a strategy based on the knocking-out of the correspondent genes”. In other words, the scientists inactivated both genes in a specific strain of mice, obtaining animals that were fully normal apart for their ability to manage the flow of cholesterol. “We proved that the concomitant absence of these two transporters – ABCA1 and G1 – impaired the efflux of cholesterol from macrophages. This turned them into foam cells, totally unable to control lipid accumulation. Eventually, there was a severe accumulation of lipidic components and a massive increase in liver and spleen volumes” explains Out.

“Interestingly – points out Theo Van Berkel – when either one of the transporters was functioning we did not observe these dramatic changes. This suggests that no other mechanisms are at work that keep the lipid balance in these cells. Hence, ABCA1 and G1 could be exploited as a desirable target when it comes to prevent vascular lipid accumulation”.

Full paper is available:
“Coexistence of Foam Cells and Hypocholesterolemia in Mice Lacking the ABC Transporters A1 and G1”
Circulation. Research (102): pp. 113-120, 2008